Two modifications of oligonucleotides have been identified that may enhance oligonucleotide affinity for complementary RNA. The 5' position of pyrimidines has been modified with a propenyl group that results in higher specific binding affinity in vitro and in enhanced antisense potency. The enhancement is about 100 fold, based on a well controlled cellular assay. Independently, the phosphate internucleotide linkage has been replaced with an achiral neutral isostere, the 3' thioformacetal. This modification results in higher in vitro binding affinity toward a complementary RNA. The aims of this project focus on efforts to combine the two modifications into one molecule, namely, to synthesize fully- substituted 3' thioformacetal oligonucleotides containing 5- (1)- propenyl)-pyrimidines and purines. This approach will be directed at HIV by synthesis of oligonucleotide analogs targeted to HIV sites that are conserved throughout all known strains. Antisense and antiviral activities will be evaluated. The ultimate goal is the identification of an analog sequence that warrants study in primate models and human trials.